rs3746190

Variant names:

• chr19-18059574-G-A
• rs3746190
• NM_005535.3:c.*34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005535.3(IL12RB1):​c.*34C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 778,530 control chromosomes in the GnomAD database, including 45,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7318 hom., cov: 32)
  • Exomes 𝑓: 0.34 (38563 hom.)
• Consequence: IL12RB1 NM_005535.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00200
• Publications: 21 publications found

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IL12RB1 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-18059574-G-A is Benign according to our data. Variant chr19-18059574-G-A is described in ClinVar as Benign. ClinVar VariationId is 328572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	NM_005535.3	MANE Select	c.*34C>T		3_prime_UTR	Exon 17 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.*34C>T		3_prime_UTR	Exon 18 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.*34C>T		3_prime_UTR	Exon 17 of 17	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.*34C>T		3_prime_UTR	Exon 17 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.*34C>T		3_prime_UTR	Exon 18 of 18	ENSP00000470788.1	P42701-1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42868 AN: 151944 Hom.: 7318 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.283

GnomAD2 exomes AF: 0.302 AC: 73419 AN: 243418 AF XY: 0.308

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.338 AC: 211489 AN: 626468 Hom.: 38563 Cov.: 0 AF XY: 0.336 AC XY: 114603 AN XY: 341138

African (AFR) AF: 0.103 AC: 1813 AN: 17684

American (AMR) AF: 0.193 AC: 8362 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 7107 AN: 20928

East Asian (EAS) AF: 0.190 AC: 6859 AN: 36030

South Asian (SAS) AF: 0.231 AC: 16064 AN: 69498

European-Finnish (FIN) AF: 0.451 AC: 23916 AN: 52984

Middle Eastern (MID) AF: 0.350 AC: 1451 AN: 4140

European-Non Finnish (NFE) AF: 0.387 AC: 134903 AN: 348840

Other (OTH) AF: 0.334 AC: 11014 AN: 33000

GnomAD4 genome AF: 0.282 AC: 42867 AN: 152062 Hom.: 7318 Cov.: 32 AF XY: 0.284 AC XY: 21085 AN XY: 74308

African (AFR) AF: 0.105 AC: 4363 AN: 41488

American (AMR) AF: 0.221 AC: 3381 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1191 AN: 3464

East Asian (EAS) AF: 0.135 AC: 699 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1110 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4971 AN: 10570

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26286 AN: 67966

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.326 Hom.: 3259

Bravo AF: 0.255

Asia WGS AF: 0.169 AC: 593 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.59
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3746190; hg19: chr19-18170384; COSMIC: COSV74045533;